Protein structure prediction for the male-specific region of the human Y chromosome

Abstract

The complete sequence of the male-specific region of the human Y chromosome (MSY) has been determined recently; however, detailed characterization for many of its encoded proteins still remains to be done. We applied state-of-the-art protein structure prediction methods to all 27 distinct MSY-encoded proteins to provide better understanding of their biological functions and their mechanisms of action at the molecular level. The results of such large-scale structure-functional annotation provide a comprehensive view of the MSY proteome, shedding light on MSY-related processes. We found that, in total, at least 60 domains are encoded by 27 distinct MSY genes, of which 42 (70%) were reliably mapped to currently known structures. The most challenging predictions include the unexpected but confident 3D structure assignments for three domains identified here encoded by the USP9Y, UTY, and BPY2 genes. The domains with unknown 3D structures that are not predictable with currently available theoretical methods are established as primary targets for crystallographic or NMR studies. The data presented here set up the basis for additional scientific discoveries in human biology of the Y chromosome, which plays a fundamental role in sex determination. D ue to an increasing gap between the overwhelming number of available protein sequences and experimentally determined protein structures, protein structure prediction has become an important venue with prolific applications in molecular biology (1). Continuous progress in this field has led to a variety of approaches applicable to structure-functional annotation of proteins. In particular, the recent advances in fold recognition (FR) and ab initio (AI) areas resulted in several methods that can reveal reliable but unexpected links between proteins (2, 3) defying standard approaches such as PSI-BLAST (4). FR͞AI tools offer opportunities to advance annotation of poorly characterized proteins, providing valuable information to guide scientific discoveries.Using a bouquet of state-of-art methods, we propose a coherent, semiautomatic strategy for structure-functional annotation of proteins and apply it to protein sequences encoded by the male-specific region of the human Y chromosome (MSY). For many years this distinctive segment of the human genome, which plays a critical role in sex determination, has been considered a functional wasteland. Complete sequence of the MSY, which comprises 95% of the length of the chromosome, revealed at least 78 protein-coding genes that collectively encode 27 distinct proteins (5). MSY genes participate in diverse processes such as skeletal growth, germ cell tumorigenesis, graft rejection, gonadal sex determination, and spermatogenic failure (6). The biological significance of the MSY has begun to surface in recent years; however, many protein-coding genes await more-detailed studies to understand their exact biological functions at the molecular level (7). Thus, comprehensive structural and functional annotation of the MSY-encoded proteins has a b...

Novel Gene Acquisition on Carnivore Y Chromosomes

“…Given the overall structural similarity of CUL4BY and CUL4BX, and the shared presence of a cullin domain, we infer that the CUL4BY encoded protein serves a related function in spermatogenesis. In humans the protein product of a unique multicopy Y chromosome gene, BPY2, is also involved in interaction with the E3 ligase complex [37], suggesting perhaps that Y chromosomes of different mammals were independently populated by genes with similar functional properties important for spermatogenesis.…”

Genetic Variants of Y Chromosome Are Associated With a Protective Lipid Profile in Black Men

“…23 However, some working hypotheses are reported in a functional analysis of predictive models of the structure of proteins encoded by MSY genes. 24 According to these hypotheses, proteins encoded by TBL1Y, USP9Y, and UTY may have regulatory functions at the level of protein-protein interactions and protein turnover. 24 In our study, the men of black African origin carrying the A alleles of both TBL1Y and USP9Y had a more favorable lipoprotein profile, characterized by lower levels of serum triglycerides and higher levels of HDL-cholesterol, thus indicating the existence of a "cardio-protective haplotype."…”

“…24 According to these hypotheses, proteins encoded by TBL1Y, USP9Y, and UTY may have regulatory functions at the level of protein-protein interactions and protein turnover. 24 In our study, the men of black African origin carrying the A alleles of both TBL1Y and USP9Y had a more favorable lipoprotein profile, characterized by lower levels of serum triglycerides and higher levels of HDL-cholesterol, thus indicating the existence of a "cardio-protective haplotype." In contrast, in white men, both from the UK and Italy, and in people of South Asian origin, the lipoprotein profiles were not affected by these genotypes.…”

Identification of the Immunodominant HY H2-Dk Epitope and Evaluation of the Role of Direct and Indirect Antigen Presentation in HY Responses

“…In contrast, material accessing the indirect pathway derives from an intact cell or cell fragments that are degraded after endocytosis or phagocytosis by host APCs. Entry into the processing machinery of host APCs is likely to be highly selective because there is no mechanism, like the DRiP process, allowing representation of all (55). Smcy (1548 aas) and Uty (1212 aas) are both large proteins, a factor that may delay proteolysis and would exclude them as primary substrates for transport into the cytosol by the Sec61 translocator (56).…”